Catalytic enantioselective synthesis of 2-aryl chromenes and related phosphoramidite ligands and catalyst compounds

ABSTRACT

Methods to access 2-aryl chromene compounds via an asymmetric catalytic process.

This application is a divisional of and claims priority to and thebenefit of application Ser. No. 15/095,855 filed Apr. 11, 2016 andissued as U.S. Pat. No. 9,624,190 on Apr. 18, 2017, which was adivisional of and claimed priority to and the benefit of applicationSer. No. 14/701,170 filed Apr. 30, 2015 and issued as U.S. Pat. No.9,309,217 on Apr. 12, 2016, which claimed priority to and the benefit ofapplication Ser. No. 61/987,308 filed May 1, 2014—each of which isincorporated herein by reference in its entirety.

This invention was made with government support under grant number P50GM086145 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Chromenes constitute a privileged class of structural motifs present ina myriad of natural products and medicinally important agents. Given theprevalence of this structural unit, there has been considerable interestin developing methods for the generation of the chromene skeleton. Whileprocedures to access racemic 2-aryl-2H-chromenes are readily available,the difficulty in generating enantioselective variants is underscored bythe scarcity of documented strategies to produce these bioactivestructures. The construction of enantioenriched 2-aryl-2H-chromenes hasbeen recently reported by You through a Ru-catalyzed ring-closingmetathesis reaction of chiral allyl ethers and also by Schaus via thechiral Brønsted acid (CBA)/Lewis acid-catalyzed addition of arylboronates to in situ formed pyrylium ions. In addition, Rueping hasrecently reported a CBA-catalyzed closure of allylic cations, but thisinnovative approach requires substitution at C4. (See, e.g., H. He, K.Y. Ye, Q. F. Wu, L. X. Dai and S. L. You, Adv. Synth. Catal., 2012, 354,1084-1094; C. Hardouin, L. Burgaud, A. Valleix and E. Doris, TetrahedronLett., 2003, 44, 435-437; P. N. Moquist, T. Kodama and S. E. Schaus,Angew. Chem. Int. Ed., 2010, 49, 7096-7100; M. Rueping, U. Uria, M. Y.Lin and I. Atodiresei, J. Am. Chem. Soc., 2011, 133, 3732-3735.)

SUMMARY OF THE INVENTION

In light of the foregoing, it is an object of the present invention toprovide methods and/or catalytic systems for the enantioselectivesynthesis of 2-aryl chromene compounds, thereby overcoming variousdeficiencies and shortcomings of the prior art, including those outlinedabove. It will be understood by those skilled in the art that one ormore aspects of this invention can meet certain objectives, while one ormore other aspects can meet certain other objectives. Each objective maynot apply equally, in all its respects, to every aspect of thisinvention. As such, the following objects can be viewed in thealternative with respect to any one aspect of this invention.

It can be an object of the present invention to provide such a synthesiswithout prerequisite, limiting starting material substitution of thesort discussed above.

It can be another object of the present invention to provide a catalysissystem and reagent alleviating undue concern over unwanted sidereactions.

It can also be an object of the present invention, alone or inconjunction with one or more of the preceding objectives, to provide anenantioselective route to the preparation of a range of therapeuticcompounds.

Other objects, features, benefits and advantages of the presentinvention will be apparent from this summary and the followingdescriptions of various preferred embodiments, and will be readilyapparent to those skilled in the art having knowledge ofenantioselective synthetic techniques. Such objects, features, benefitsand advantages will be apparent from the above as taken into conjunctionwith the accompanying examples, data, figures and all reasonableinferences to be drawn therefrom, alone or with consideration of thereferences incorporated herein.

In part, the present invention can be directed to a method forasymmetric synthesis of a 2-aryl chromene compound. Such a method cancomprise providing a reaction medium comprising ano-arylallyl-substituted phenoxy ester starting material of a formula

wherein X can be selected from alkylcarbonyl and alkylcarbonyl moieties,LG can be a leaving group selected from alkoxycarbonyl groups, R can beselected from H, halo, alkyl and alkoxy moieties, multiple moieties andcombinations thereof and Ar can be a moiety selected from aryl andsubstituted aryl moieties, such aryl substituents as can be selectedfrom halo, alkyl, alkoxy and nitro substituents, multiple suchsubstituents and combinations thereof; introducing a palladium (II)catalyst precursor compound and a phosphoramidite ligand compound tosuch a reaction medium; reacting such a starting material with a basecomponent to promote intramolecular cyclization of such a reactedstarting material and provide an asymmetric 2-aryl chromene compound ofa formula

In certain non-limiting embodiments, such a phosphoramidite ligandcompound can be of a formula

wherein R and R¹ can be independently selected from alkyl, phenyl,phenylalkyl and cycloalkyl moieties, and where R and R¹ can togetherprovide a divalent alkylene moiety; each R² can be independentlyselected from methyl and ethyl moieties, and where the R² moietiestogether can provide a divalent moiety selected from alkylene andalkyl-substituted alkylene moieties; and each Ar can be independentlyselected from phenyl and substituted phenyl moieties. In certain suchembodiments, each of R and R¹ can be a chiral CH(CH₃)C₆H₅ moiety. Incertain other such embodiments, R and R¹ can together provide a divalent(CH₂)_(m) moiety, wherein m can be an integer selected from 4-6.

Regardless, without limitation, each Ar can be an alkyl-substitutedphenyl moiety. In certain embodiments, such a phosphoramidite ligandcompound can be of a formula

wherein each R³ can be independently selected from methyl and ethylmoieties and combinations thereof, and each n can independently be aninteger selected from 1-3. In certain such non-limiting embodiments,each R³ can be ethyl and each n can be 2, to provide such a ligandcompound with 3,5-diethyl substituted phenyl moieties.

With respect to an aforementioned ester starting material, such an Armoiety can be selected from substituted phenyl and naphthyl moieties. Incertain non-limiting embodiments, such a phenyl moiety can besubstituted with one or more halo, alkyl, alkoxy, nitro and haloalkylsubstituents, multiple such substituents and combinations thereof.Regardless, X can be selected from acetyl and benzoyl moieties, and LGcan be selected from acetyloxy and benzoyloxy moieties. In certain suchembodiments, X can be acetyl and LG can be acetyloxy, to provide abis-acetate starting material. Irrespective of ester identity, chromenesynthesis can proceed with a phosphoramidite ligand of the sortdescribed above, wherein, for instance, R and R¹ can together provide adivalent (CH₂)_(m) moiety, where m can be an integer selected from 4-6,and each Ar can be an alkylated phenyl moiety.

In part, the present invention can also be directed to a method of usingintramolecular cyclization for enantioselective synthesis of a2-aryl-2H-chromene compound. Such a method can comprise providing areaction medium comprising an o-arylallyl-substituted bis-acetatecompound of the sort described herein, a base component, a palladium(II) catalyst precursor compound and a chiral phosphoramidite ligandcompound of the sort discussed above or illustrated elsewhere herein(e.g., without limitation, L3 or L4, below); and deacylating such abis-acetate compound to promote intramolecular cyclization and C—O bondformation, to enantioselectively provide a compound of a formula

wherein R is selected from H, halo, alkyl and alkoxy moieties, and Ar isselected from phenyl, substituted phenyl and naphthyl moieties, wherebysuch a compound can have an enantiomeric ratio of greater than about60:40 for said enantiomer.

In certain non-limiting embodiments, such a ligand compound can be ofthe sort described above and illustrated elsewhere herein. For instance,R and R¹ can together provide a divalent (CH₂)_(m) moiety, wherein m isan integer selected from 4-6. Alternatively, R can be alkyl and R¹ canbe cycloalkyl. Regardless of R/R¹ identity, each Ar can be analkyl-substituted phenyl moiety. In certain embodiments, each Ar can bea dialkyl-substituted phenyl moiety, such as a 3,5-dimethyl- or a3,5-diethyl-substituted phenyl moiety. Use of such ligand compounds inconjunction with the present method(s) can provide a 2-aryl-2H-chromenecompound with an enantiomeric ratio of greater than about 90:10 for oneenantiomer thereof.

In part, the present invention can also be directed to compositionscomprising compounds of a formula

wherein R can be selected from H, halo, alkyl and alkoxy moieties,multiple such moieties and combinations thereof and Ar can be selectedfrom phenyl and substituted phenyl moieties, such phenyl substituents ascan be selected from halo, alkyl, alkoxy, nitro and haloalkylsubstituents, multiple such substituents and combinations thereof, sucha composition as can comprise at least about 70% an enantiomer of aformula

In certain non-limiting embodiments, such a moiety can be selected frommethyl, methoxy, fluoro, chloro, nitro and dichlorosubstituted phenylmoieties, and such a composition can comprise at least about 90% of suchan enantiomer.

Accordingly, the present invention can, in part, be directed to a ligandcompound of a formula

wherein R and R¹ can be independently selected from alkyl, phenyl,phenylalkyl and cycloalkyl moieties, and where R and R¹ can togetherprovide a divalent alkylene moiety; each R² can be independentlyselected from methyl and ethyl moieties, and where the R² moietiestogether can provide a divalent moiety selected from alkylene andalkyl-substituted alkylene moieties; and each Ar can be independentlyselected from phenyl and substituted phenyl moieties. In certain suchembodiments, each of R and R¹ can be a chiral CH(CH₃)C₆H₅ moiety. Incertain other such embodiments, R and R¹ can together provide a divalent(CH₂)_(m) moiety, wherein m can be an integer selected from 4-6. Invarious other non-limiting embodiments, R can be a methyl moiety and R¹can be a cyclohexyl moiety, or R and R¹ can together provide a divalent(CH₂)₅ moiety; each R² can be a methyl moiety or each R² can togetherprovide a divalent C(CH₃)₂ moiety; and each Ar can be independentlyselected from phenyl, methyl- and polymethyl-substituted phenyl, andethyl and polyethyl-substituted phenyl moieties. As discussed below,such a ligand compound can be complexed, bound, coordinated or otherwisecoupled to a palladium metal component. Such complexation and the likecan provide a palladium catalyst of the sort described below and usefulin conjunction with the synthetic method(s) of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the office upon request and paymentof the necessary fee.

FIGS. 1-3. FIG. 1. Schematic reaction design for 2-aryl-2H-chromenes,illustrating methods of this invention and, without limitation,representative compounds available therefrom. FIG. 2. Proposed reactionpathway. FIG. 3. Molecular structure of [Pd(η³-1,3-diphenylallyl){(S,S)-L3g}]BF₄. ORTEP at 80% probability with hydrogen atoms and BF₄omitted for clarity.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

By way of developing new approaches to construct pyran and relatedmotifs, an investigation was begun relating to substrate/catalystactivation combinations to access chromenes via an asymmetric catalyticprocess. After extensive exploration with substrates such as 1 (notshown), easily accessed from chalcone precursors, the use of eitherorganocatalysis or transition metal catalysis led to an invariableobservation: compounds with unprotected ortho-substituted phenols weretypically unstable and often underwent uncatalyzed cyclizations toracemic chromenes rapidly (eq 1).

With this data in hand and the background reaction a concern, thefollowing reaction design factors were considered: a) promote phenolformation during the course of the reaction, b) avoid any backgroundreactions by activating an allylic system through a chiral metal complexor organocatalytic mechanism, and c) promote a 6-endo-trig type closureof the phenol/phenoxide with control of the absolute stereochemistry.Based on this logic, it was envisaged that 2-aryl-2H-chromenes could beconstructed through a 6-endo-trig Pd-catalyzed asymmetric allylicsubstitution (FIG. 1). While Pd-catalyzed allylic alkylation is aprominent strategy for C—C and C-heteroatom bond formation, it isbelieved there are no reports of a general asymmetric 6-endo-trigvariant.

This investigation began by combining bis-acetate 1a with potassiumcarbonate, a palladium source or catalyst precursor compound such aspalladium dibenzylideneacetone, Pd₂(dba)₃, and a variety ofphosphoramidite ligands. (Various other palladium sources can be used,as would be understood by those skilled in the art and made aware ofthis invention.) Although monodentate phosphoramidites are efficientchiral ligands in promoting various Pd-catalyzed reactions, theirapplication in asymmetric allylic substitutions remains underdeveloped.Initial ligand screens included BINOL-, SIPHOS-, and TADDOL-derivedphosphoramidites. Preliminary experiments with BINOL-derived ligand L1aprovided chromene 2a in quantitative yield with an encouraging 69:31enantiomeric ratio (Table 1, entry 1). Unfortunately, modification ofthe amine constituent to piperidine, dimethylamine, 1-phenylethylamine(results not shown) or bis[(S)-1-phenethyl]amine (entry 2), wasdetrimental to both the conversion and enantioselectivity. Themodification of the ligand backbone to SIPHOS-derived ligand(R_(a),R,R)-L2 and TADDOL-derived ligand L3a resulted in significantlyimproved levels of enantioselectivity (entries 3 and 5, respectively).Interestingly, the diastereomer (S_(a),R,R)-L2 (entry 4) affordedracemic chromene product, suggesting a mismatch of stereogenic elements.

TABLE 1 Optimization of reaction conditions.

entry ligand Ar NRR¹ time^(a) er^(b) 1 L1a — N(i-Pr)₂  2 h 69:31 2 L1b —N((S)—CH(Me)(Ph))₂ 21 h 57:43 3 (R_(a), R, R)-L2 — —  1 d 79:21 4(S_(a), R, R)-L2 — —  1 d 50:50 5 L3a Ph N((S)—CH(Me)(Ph))₂ 12 h 74:26 6L3b Ph N(Me)₂  2 h 60:40 7 L3c Ph N(i-Pr)₂  4 h 65:35 8 L3d Ph N(CH₂)₅ 2 h 82:18 9 L4 Ph N(CH₂)₅  3 h 53:47 10 L3e 2-Me-C₆H₄ N(CH₂)₅ 12 h85:15 11 L3f 3-Me-C₆H₄ N(CH₂)₅ 19 h 90:10 12 L3g 3,5-Me-C₆H₃ N(CH₂)₅ 38h 93:7  13 L3h 3,5-Me-C₆H₃ N(CH₂)₄  2 d 71:29 14 L3i 3,5-Me-C₆H₃ N(CH₂)₆ 2 d 93:7  15 L3j 3,5-Me-C₆H₃ N(Me)(Cy) 19 h 93:7  16 L3k 3,5-Et-C₆H₃N(CH₂)₅ 19 h 95:5 

^(a)Time to reach 100% conversion as measured by¹H NMR (500 MHz). Longerreactions did not provide side products. ^(b)Enantiomeric ratiodetermined by HPLC.

Due to the shortened reaction time with ligand L3a compared to L2 andthe opportunity to rapidly evaluate a wide range of TADDOL-derivedligands, efforts were focused on the optimization of this ligandbackbone. A variety of N-substituents were evaluated, including achiraland sterically less demanding amine moieties (entry 6-8). In comparisonto ligand L3a, other acyclic amines such as dimethylamine (entry 6) anddiisopropyl amine (entry 7) resulted in decreased enantioselectivity,while replacement with the more rigid piperidinyl substituent affordedchromene 2a with improved selectivity (82:18 er, entry 8). To understandthe effects of ligand rigidity on engendering enantioselection, theisopropylidene acetal of L3 was substituted with an acyclic dimethylether motif. With the less rigid L4 as the ligand, chromene 2a wasfurnished with low enantioselectivity (entry 9).

Another point of variation of the TADDOL-derived ligands lies in thesubstitution about the arene rings. The examination of variousaryl-substituted TADDOL ligands (entry 10-12) revealed thatenantioselectivity can be enhanced through the placement and positioningof methyl groups on the aryl ring, culminating in a 93:7 er attained forligand L3g (entry 12). The effects of the nitrogen substituent were thenrevisited. Interestingly, the replacement of the piperidine with apyrrolidine resulted in a significant decrease in enantioselectivity(entry 13), while incorporation of a 7-membered azepane maintained thepreviously observed 93:7 er (entry 14). Efforts to increaseenantioselectivity by utilizing acyclic amines were ineffective (entry15). Finally, the incorporation of ethyl groups at the 3- and 5-positionof the aryl ring was explored. It was interesting to find that with thisligand (L3k), chromene 2a was obtained in 71% isolated yield with 95:5er (entry 16).

TABLE 2 Substrate scope^(a).

^(a)See Supporting Information for details. Yield of isolated productafter chromatography. Enantiomeric ratio determined by HPLC analysis.

With selective conditions developed, several bis-acetate substrates wereevaluated (Table 2). The high levels of enantioselectivity observed for2a were maintained with extended aromatic moieties (2b and 2c).Electron-donating groups on the styrenyl component were alsowell-tolerated, with methyl substitution in the ortho- or para-positions(2d and 2e, respectively) affording the chromene products in good yieldand excellent enantioselectivity. The electron-rich 3-methoxysubstituted cyclization precursor also performed well in this reaction,generating chromene 2f (78%, 94:6 er).

The incorporation of electron-withdrawing (2g-2l) substituents aroundthe pendant aromatic ring was also accommodated. Furthermore, it wasfound that the electronegative fluorine substituent can occupy variouspositions while maintaining high er. The erosion of enantioselectivitywas observed with substrates possessing a trifluoromethyl, dichloro, orthe strongly electronegative nitro group (2j-2l), but a fluorinesubstituent was tolerated at various positions (2m-n) with respect tothe incipient phenoxide moiety. The electron-donating methoxy group wasalso accommodated, albeit with a slight decrease in enantioselectivity(2o). Additionally, the preparation of chromene 2p indicates that thissystem tolerates moderate substitution adjacent to the phenoxide.

Without limitation to any one theory or mode of operation, the completeconversion of racemic substrates 1 to the enantioenriched chromenesindicates that a dynamic kinetic asymmetric transformation (DYKAT) mightbe operative. Since both enantiomers of the starting material must gothrough a common intermediate, and the unsymmetrical 1,3-disubstitutedallyl substrate precludes racemization through a palladium π-σ-π allylrearrangement, the generation of an achiral ortho-quinone methideintermediate (4) can be proposed to account for the high levels ofenantioselectivity observed for the chromene products (FIG. 2).

Current understanding of the reaction contemplates subjection of eitherenantiomer of 1a to potassium carbonate and methanol, which rapidlyproduces the nucleophilic phenoxide in situ (±3, Path A). Thisdeacylation promotes ejection of the secondary acetate to form theachiral trans o-quinone methide (o-QM, 4a). A subsequent coordinationand addition of the chiral palladium complex generates the π allylintermediate (5a) which undergoes intramolecular attack of the proximalphenoxide after bond rotation to achieve the proper conformation (6).For this pathway, the rate of o-QM formation is faster than addition ofthe palladium.ligand complex to ±3 (or ±1). If this is not the case,then an alternative potential pathway could be operative (Path B). Thisprocess involves the generation of diasteromeric π allyl palladiumcomplexes (5a or 5b) from each enantiomer of 3. While one of theseadditions would be the “matched” case, a rapid interconversion betweenthe diasteromeric intermediates is required so the “mismatched” complexundergoes smooth conversion to the observed enantiomer (2a) vs. theundesired isomer (ent-2a). Possible mechanisms for this involvegeneration of the achiral o-QM or direct addition of the palladiumcomplex. Again, without limitation, Path A is currently favoured due tothe lack of observed correlation between enantioselectivity and catalystconcentration, which disfavors Path B. Additionally, the use ofbis-benzoylated substrates (vs. acetates) proceeds at the approximatelythe same rate with the similar levels of er and yield.

It was undertaken to further elucidate the structure of the Pd(II)-L3kcomplex and its interaction with the bis-acetate substrate 1a. Towardthat end, X-ray quality crystals of the related Pd(II) complex has beensolved using ligand L3g in conjunction with 1,3-diphenyl allyl acetateas a substrate surrogate incapable of closure (FIG. 2). The structureshows that the phosphoramidite ligand L3g is coordinated to the Pd(II)center through its phosphorus center and a single aryl ring. Thisη²-arene stabilization results in the observed 1:1phosphoramidite-Pd(II) complex and supports mono-coordination of a bulkyligand to the palladium. The conversion and enantiomeric ratio of thechromene product, as well as reaction rate, remained unperturbed upon areduction in ligand loading from 8 to 4 mol % (i.e., 2:1 to 1:1phosphoramidite:Pd).

To highlight the potential of this new approach, it was thought toundertake the synthesis of catechin 8, which has demonstratedanti-staphylococcal activity due to the ability to reverse methicillinresistance in strains of drug resistant Staph. aureus. Interestingly,this catechin analog has increased activity compared to the parent(−)-epicatechin gallate, which bears additional hydroxyl groups on thecatechin core (7). The regioselective hydroboration of 2a deliveredchromanol 7 with 9:1 dr favoring the desired anti relationship. Theesterification of chromanol 7 with tri-OBn gallic acid chloride followedby hydrogenolysis afforded 8 in 65% yield over the two steps. In asecond vignette, the synthesis of hydroxyflavanone 10 was accomplished.The racemate of this compound exhibited promising levels of inhibitionof M. tuberculosis H37Rv. Application of the present methodology allowsaccess to enantioenriched 10 and could facilitate improvedstructure-activity relationship (SAR) studies. A cis-dihydroxylation ofchromene 2i (94:6 er) using 3 mol % OsO₄ and NMO provided2,3-trans-3,4-phenylchromandiol (5.6:1 dr). A recrystallization of themixture provided a single diastereomer with >99:1 er. The exposure ofdiol 9 to MnO₂ resulted in the desired benzylic oxidation, withoutepimerization at C-3, to furnish 10 in 59% yield (Scheme 1).

As demonstrated, the present invention provides a catalyticenantioselective method for the synthesis of 2-aryl-2H-chromenes. Aligand structure-selectivity relationship study resulted in thedevelopment of a novel monodentate phosphoramidite system that enabledthe synthesis of these privileged heterocycles with high yield andenantioselectivity. Crystallographic analysis provides mechanisticsupport that aryl ligand-metal interactions provide unanticipatedadditional rigidity in competing diastereomeric transition states whichpromotes the high levels of enantioselectivity for the newly formed C—Obond.

Examples of the Invention

The following non-limiting examples and data illustrate various aspectsand features relating to the methods and compounds of the presentinvention, including the preparation of various 2-aryl chromenecompounds, as are available through the synthetic methodologiesdescribed herein. In comparison with the prior art, the present methodsand compounds provide results and data which are surprising, unexpectedand contrary thereto. While the utility of this invention is illustratedthrough the use of several arylallyl-substituted phenoxy ester startingmaterials and phosphoramidite catalyst compounds and respectivesubstituents thereon, it will be understood by those skilled in the artthat comparable results are obtainable with various other startingmaterials, catalyst compounds and respective substituents, as arecommensurate with the scope of this invention.

General Information

All reactions were carried out under a nitrogen atmosphere inflame-dried glassware with magnetic stirring. THF, toluene, anddichloromethane were purified by passage through a bed of activatedalumina. Reagents were purified prior to use unless otherwise statedfollowing the guidelines of Perrin and Armarego. (D. D. Perrin and W. L.F. Armarego, Purification of Laboratory Chemicals; 3rd Ed., PergamonPress, Oxford. 1988.) Purification of reaction products was carried outby flash chromatography using EM Reagent or Silicycle silica gel 60(230-400 mesh). Analytical thin layer chromatography was performed on EMReagent 0.25 mm silica gel 60-F plates. Visualization was accomplishedwith UV light and ceric ammonium nitrate stain or potassium permanganatestain followed by heating. Infrared spectra were recorded on a BrukerTensor 37 FT-IR spectrometer. ¹H-NMR spectra were recorded on a BrukerAvance 500 MHz w/ direct cryoprobe (500 MHz) spectrometer and arereported in ppm using solvent as an internal standard (CDCl₃ at 7.26ppm). Data are reported as (ap=apparent, s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, b=broad; coupling constant(s) in Hz;integration). Proton-decoupled ¹³C-NMR spectra were recorded on a BrukerAvance 500 MHz w/ direct cryoprobe (125 MHz) spectrometer and arereported in ppm using solvent as an internal standard (CDCl₃ at 77.2ppm). Mass spectra data were obtained on a Waters Acquity SingleQuadrupole ESI Spectrometer, Micromass Quadro II Spectrometer andAgilent 7890 GC-TOF.

Benzaldehyde and 2′-hydroxyacetophenone derivatives were obtained fromcommercial sources (Sigma Aldrich, Oakwood). Chalcones andphosphoramidites were prepared according to published procedures. (See,L. D. Chiaradia, A. Mascarello, M. Purificacao, J. Vernal, M. N. S.Cordeiro, M. E. Zenteno, A. Villarino, R. J. Nunes, R. A. Yunes, and H.Terenzi, Bioorg. Med. Chem. Lett., 2008, 18, 6227-6230; and A. Alexakis,J. Burton, J. Vastra, C. Benhaim, X. Fournioux, A. van den Heuvel, J. M.Leveque, F. Maze, and S. Rosset, Eur. J. Org. Chem., 2000, 4011-4027,respectively.)

Example 1 General Procedure for the Synthesis of 2′-HydroxychalconeDerivatives

2′-Hydroxychalcones were prepared using a modified literature procedure.(L. D. Chiaradia, A. Mascarello, M. Purificacao, J. Vernal, M. N. S.Cordeiro, M. E. Zenteno, A. Villarino, R. J. Nunes, R. A. Yunes, and H.Terenzi, Bioorg. Med. Chem. Lett., 2008, 18, 6227-6230.) Into a roundbottom flask equipped with magnetic stirring bar was dissolvedacetophenone derivative (15 mmol, 1 equiv) in methanol (100 mL) and 50%w/v KOH (17 mL). The reaction was stirred at 0° C. for 30 min. Thealdehyde (18 mmol, 1.2 equiv) was added in one portion, and the mixturewas stirred at 23° C. for 12-24 h. The solution was neutralized with 12M HCl. The precipitate was removed by vacuum filtration, washed withwater, dried, and recrystallized from methanol ordichloromethane/hexanes. When no precipitate was formed uponneutralization, the solution was extracted with EtOAc, and the combinedorganics were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography using 10%EtOAc/hexanes or recrystallization with hot methanol to afford thechalcones as a yellow solid.

Example 2 General Procedure for the Synthesis of Bis-Acetates

Into a round bottom flask equipped with magnetic stir bar was loaded2′-hydroxychalcone derivative (2.5 mmol, 1 equiv), CeCl₃.7H₂O (5.5 mmol,2.2 equiv), ethanol (200 proof, 8.8 equiv), and THF (0.1 M 25 mL). Themixture was cooled to 0° C. before NaBH₄ (5.5 mmol, 2.2 equiv) was addedin one portion and allowed to slowly warmed to 23° C. Upon consumptionof the 2′-hydroxychalcone, 4-dimethylaminopyridine (3.75 mmol, 1.5equiv), pyridine (37.5 mmol, 15 equiv), and acetic anhydride (37.5 mmol,15 equiv) were successively added. The reaction was stirred for 12-18 hand concentrated. The unpurified residue was taken up in EtOAc andquenched with a saturated solution of sodium bicarbonate. The layerswere separated and the aqueous layer was back extracted with EtOAc. Thecombined organics were washed with DI H₂O, saturated copper(II) sulfate,and brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography usingEtOAc/hexanes to afford the corresponding bis-acetates.

Example 3

(E)-1-(2-Acetoxy-3-methylphenyl)-3-phenylallyl acetate (1a)

Prepared according to the general procedure using(E)-2-(1-hydroxy-3-phenylallyl)-phenol. The residue was purified byflash chromatography using 15% EtOAc/hexanes to afford 1a as a clearcrystal (450 mg, 74%). Analytical data for 1a: ¹H NMR (500 MHz, CDCl₃) δ7.52 (dt, J=7.7, 1.5 Hz, 1H), 7.39-7.34 (m, 3H), 7.35-7.23 (m, 4H), 7.11(dt, J=8.1, 1.3 Hz, 1H), 6.62 (d, J=16.0, 1H), 6.61 (d, J=6.5 Hz, 1H),6.35 (dd, J=15.8, 6.6 Hz, 1H), 2.32 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125MHz, CDCl₃) δ 170.0, 169.5, 148.4, 136.2, 132.9, 131.1, 129.5, 128.7,128.6, 128.3, 126.8, 126.5, 126.2, 123.3, 71.3, 21.3, 21.2; IR (film):3061, 3027, 2938, 1765, 1738, 1650, 1586, 1491, 1452, 1369, 1233, 1197,1173, 1098, 1063, 1015, 964, 911, 877 cm⁻¹; LRMS (ESI): Mass calculatedfor [M+H]⁺ C₁₉H₁₉O₄: 311.1; found: 311.1.

Example 4

(E)-2-(1-Acetoxy-3-(naphthalen-1-yl)allyl)phenyl acetate (1b)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1b as a colorless oil (290 mg, 40%). Analytical data for 1b: ¹H NMR (500MHz, CDCl₃) δ 8.05 (d, J=8.6, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.79 (d,J=8.1 Hz, 1H), 7.59 (dd, J=7.8, 1.7 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H),7.55-7.47 (m, 2H), 7.49-7.39 (m, 3H), 7.34 (td, J=7.6, 1.3 Hz, 1H), 7.17(dd, J=8.0, 1.3 Hz, 1H), 6.76 (dd, J=6.5, 1.3 Hz, 1H), 6.41 (dd, J=15.6,6.5 Hz, 1H), 2.36 (s, 3H), 2.18 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ170.0, 169.6, 148.5, 134.0, 133.7, 131.3, 131.1, 130.4, 129.6, 129.4,128.8, 128.7, 128.6, 126.5, 126.4, 126.0, 125.7, 124.3, 123.8, 123.4,71.5, 21.4, 21.2; IR (film): 3060, 3046, 3014, 2936, 1765, 1737, 1369,1233, 1198 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺ C₂₃H₂₁O₄: 361.1;found: 361.0.

Example 5

(E)-2-(1-Acetoxy-3-(naphthalen-2-yl)allyl)phenyl acetate (1c)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1c as a colorless oil (250 mg, 57%). Analytical data for 1c: ¹H NMR (500MHz, CDCl₃) δ 7.81-7.73 (m, 4H), 7.57 (ddd, J=9.4, 8.2, 1.7 Hz, 2H),7.49-7.42 (m, 2H), 7.38 (td, J=7.6, 1.7 Hz, 1H), 7.30 (td, J=7.6, 1.3Hz, 1H), 7.12 (dd, J=8.1, 1.2 Hz, 1H), 6.78 (d, J=15.9 Hz, 1H), 6.67(dd, J=6.5, 1.3 Hz, 1H), 6.47 (dd, J=15.9, 6.4 Hz, 1H), 2.33 (s, 3H),2.14 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 169.6, 148.4, 133.63,133.59, 133.3, 133.0, 131.1, 129.5, 128.8, 128.4, 128.2, 127.8, 127.2,126.54, 126.51, 126.49, 126.3, 123.6, 123.3, 71.3, 21.3, 21.2; IR(film): 3057, 2936, 2854, 1766, 1737, 1651, 1607, 1507, 1369, 1233,1198, 1174 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺ C₂₃H₂₁O₄: 361.1;found: 361.3.

Example 6

(E)-2-(1-Acetoxy-3-(o-tolyl)allyl)phenyl acetate (1d)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(o-tolyl)prop-2-en-1-one. The residue waspurified by flash chromatography using 15% EtOAc/hexanes to afford 1d asa colorless oil (290 mg, 40%). Analytical data for 1d: ¹H NMR (500 MHz,CDCl₃) δ 7.53 (dd, J=7.7, 1.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.37 (td,J=7.8, 1.7 Hz, 1H), 7.28 (td, J=7.6, 1.2 Hz, 1H), 7.19-7.09 (m, 4H),6.85 (dd, J=15.9, 1.3 Hz, 1H), 6.62 (dd, J=6.6, 1.3 Hz, 1H), 6.24 (dd,J=15.7, 6.6 Hz, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 169.9, 169.4, 148.3, 135.8, 135.2, 131.1, 130.9,130.4, 129.4, 128.6, 128.0, 127.4, 126.4, 126.2, 125.8, 123.2, 71.5,21.2, 21.1, 19.8; IR (film): 3098, 3063, 3017, 2912, 2860, 1924, 1724,1719, 1572, 1463, 1426 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺C₂₀H₂₁O₄: 325.1; found: 325.5.

Example 7

(E)-2-(1-Acetoxy-3-(p-tolyl)allyl)phenyl acetate (1e)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one. The residue waspurified by flash chromatography using 15% EtOAc/hexanes to afford 1e asa colorless oil (170 mg, 62%). Analytical data for 1e: ¹H NMR (500 MHz,CDCl₃) δ 7.52 (dd, J=7.7, 1.7 Hz, 1H), 7.36 (td, J=7.7, 1.7 Hz, 1H),7.29-7.26 (m, 3H), 7.11 (d, J=8.1 Hz, 2H), 7.10 (dd, J=8.3, 1.3 Hz, 1H),6.60 (d, J=7.5 Hz, 1H), 6.59 (d, J=15.4 Hz, 1H), 6.34-6.25 (m, 1H), 2.33(s, 3H), 2.31 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0,169.5, 148.4, 138.2, 133.4, 132.9, 131.2, 129.4, 128.7, 126.7, 126.4,125.1, 123.3, 71.4, 21.4, 21.3, 21.2; IR (film): 3087, 3023, 2973, 2921,2858, 1777, 1769, 1588, 1371, 1282, 1245 cm⁻¹; LRMS (ESI): Masscalculated for [M+H]⁺ C₂₀H₂₁O₄: 325.1.

Example 8

(E)-2-(1-Acetoxy-3-(3-methoxyphenyl)allyl)phenyl acetate (1f)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1f as a colorless oil (330 mg, 42%). Analytical data for 1f: ¹H NMR (500MHz, CDCl₃) δ 7.52 (dd, J=7.7, 1.7 Hz, 1H), 7.37 (ddd, J=8.1, 7.4, 1.7Hz, 1H), 7.28 (td, J=7.8, 1.5 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 7.11 (dd,J=8.1, 1.2 Hz, 1H), 6.97 (dt, J=7.6, 1.2 Hz, 1H), 6.90 (dd, J=2.6, 1.5Hz, 1H), 6.81 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 6.61 (d, J=6.5 Hz, 1H),6.60 (d, J=15.9 Hz, 1H), 6.34 (dd, J=15.6, 6.7 Hz, 1H), 3.80 (s, 3H),2.32 (s, 3H), 2.11 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.7, 169.3,159.6, 148.1, 137.3, 132.5, 130.8, 129.5, 129.2, 128.5, 126.25, 126.20,123.0, 119.2, 113.7, 111.7, 70.9, 55.1, 21.0, 20.9; IR (film): 3063,3038, 3005, 2959, 2940, 1766, 1599, 1489, 1466, 1370, 1234, 1042 cm⁻¹;LRMS (ESI): Mass calculated for [M+H]⁺ C₂₀H₂₁O₅: 341.1; found 341.1.

Example 9

(E)-2-(1-Acetoxy-3-(2-fluorophenyl)allyl)phenyl acetate (1g)

Prepared according to the general procedure using(E)-3-(2-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1g as a colorless oil (229 mg, 47%). Analytical data for 1g: ¹H NMR (500MHz, CDCl₃) δ 7.52 (dd, J=7.7, 1.7 Hz, 1H), 7.42 (td, J=7.7, 1.7 Hz,1H), 7.37 (td, J=7.7, 1.7 Hz, 1H), 7.28 (dd, J=7.6, 1.3 Hz, 1H), 7.22(dddd, J=8.1, 7.1, 5.2, 1.8 Hz, 1H), 7.11 (dd, J=8.2, 1.3 Hz, 1H), 7.08(td, J=7.6, 1.2 Hz, 1H), 7.03 (ddd, J=10.8, 8.3, 1.2 Hz, 1H), 6.80 (dd,J=16.3, 1.2 Hz, 1H), 6.61 (dd, J=6.6, 1.3 Hz, 1H), 6.43 (dd, J=16.1, 6.5Hz, 1H), 2.33 (s, 3H), 2.12 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9,169.5, 160.5 (d, J=249.8 Hz), 148.4, 130.9, 129.56 (d, J=8.6 Hz),129.56, 128.74 (d, J=5.5 Hz), 128.69, 127.8 (d, J=3.5 Hz), 126.5, 125.1(d, J=3.6 Hz), 124.3 (d, J=3.6 Hz), 124.0 (d, J=12.0 Hz), 123.3, 115.9(d, J=22.0 Hz), 71.3, 21.3, 21.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −117.57; IR(film): 3064, 3040, 2935, 2853, 1766, 1741, 1609, 1579, 1488, 1455,1370, 1231, 1199, 1174, 1096, 1066, 1016, 968 cm⁻¹; LRMS (ESI): Masscalculated for [M+H]⁺ C₁₉H₁₈FO₄: 329.1; found: 329.2.

Example 10

(E)-2-(1-Acetoxy-3-(4-fluorophenyl)allyl)phenyl acetate (1h)

Prepared according to the general procedure using(E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1h as a white solid (285 mg, 39%). Analytical data for 1h: ¹H NMR (500MHz, CDCl₃) δ 7.51 (dd, J=7.7, 1.7 Hz, 1H), 7.40-7.30 (m, 3H), 7.29 (dd,J=7.6, 1.3 Hz, 1H), 7.10 (dd, J=8.1, 1.3 Hz, 1H), 6.99 (t, J=8.7 Hz,2H), 6.59-6.55 (m, 2H) 6.26 (dd, J=15.6, 6.9 Hz, 1H), 2.31 (s, 3H), 2.11(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 169.5, 162.7 (d, J=247.8 Hz),148.3, 132.3 (d, J=3.2 Hz), 131.8, 131.0, 129.5, 128.7, 128.4 (d, J=8.0Hz), 126.5, 126.0 (d, J=2.3 Hz), 123.3, 115.7 (d, J=21.7 Hz), 71.2,21.3, 21.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.62; IR (film): 3041, 2937,1769, 1765, 1736, 1729, 1655, 1601, 1509, 1489, 1453, 1431, 1371, 1297,1158, 1096, 1040, 1012, 970 cm⁻¹; LRMS (ESI): Mass calculated for [M−H]⁻C₁₉H₁₆FO₄: 327.1; found: 327.0.

Example 11

(E)-2-(1-Acetoxy-3-(3-chlorophenyl)allyl)phenyl acetate (1i)

Prepared according to the general procedure using(E)-3-(3-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1i as a colorless oil (683 mg, 64%). Analytical data for 1i: ¹H NMR (500MHz, CDCl₃) δ 7.53 (dd, J=7.7, 1.6 Hz, 1H), 7.41 (dd, J=7.7, 1.7 Hz,1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (td, J=7.6, 1.2 Hz, 1H), 7.26 (m, 3H),7.14 (dd, J=8.1, 1.3 Hz, 1H), 6.63 (dd, J=6.2, 1.3 Hz, 1H), 6.58 (dd,J=15.9, 1.4 Hz, 1H), 6.39 (dd, J=15.9, 6.3 Hz, 1H), 2.35 (s, 3H), 2.14(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9, 169.5, 148.4, 138.0, 134.7,131.3, 130.8, 130.0, 129.6, 128.7, 128.2, 127.8, 126.7, 126.5, 125.1,123.3, 70.9, 21.25, 21.18; IR (film): 3064, 3038, 2936, 2850, 1765,1739, 1593, 1566, 1489, 1453, 1428, 1369, 1232, 1198, 1174, 1096, 1077,1066, 1015, 962, 911, 777, 757 cm⁻¹; LRMS (ESI): Mass calculated for[M+H]⁺ C₁₉H₁₈ClO₄: 345.1; found: 345.1.

Example 12

(E)-2-(1-Acetoxy-3-(4-(trifluoromethyl)phenyl)allyl)phenyl acetate (1j)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one.The residue was purified by flash chromatography using 15% EtOAc/hexanesto afford 1j as a colorless oil (230 mg, 49%). Analytical data for 1j:¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, J=8.1 Hz, 2H), 7.50 (dd, J=7.7, 1.7Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.38 (td, J=7.8, 1.7 Hz, 1H), 7.29 (td,J=7.5, 1.3 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.63 (d, J=15.9 Hz,1H), 6.62 (d, J=6.5 Hz, 1H) 6.43 (dd, J=15.9, 6.2 Hz, 1H), 2.32 (s, 3H),2.13 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9, 169.5, 148.4, 139.7,131.2, 130.7, 130.0 (d, J=32.4 Hz), 129.7, 129.0, 128.8, 127.0, 126.6,125.7 (q, J=3.8 Hz), 124.2 (d, J=272.0 Hz), 123.4, 70.8, 21.3, 21.2; ¹⁹FNMR (376 MHz, CDCl₃) δ −62.62; IR (film): 3085, 3044, 2937, 1926, 1782,1726, 1657, 1615, 1587, 1494, 1455, 1415, 1365, 1316, 1282, 1252, 1137,1097 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺ C₂₀H₁₈F₃O₄: 379.1;found: 379.2.

Example 13

(E)-2-(1-Acetoxy-3-(3,4-dichlorophenyl)allyl)phenyl acetate (1k)

Prepared according to the general procedure using its(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one. Theresidue was purified by flash chromatography using 15% EtOAc/hexanes toafford 1k as a colorless oil (230 mg, 28%). Analytical data for 1k: ¹HNMR (500 MHz, CDCl₃) δ 7.39 (dd, J=7.7, 1.7 Hz, 1H), 7.35 (s, 1H),7.31-7.26 (m, 2H), 7.22-7.14 (m, 1H), 7.08 (dd, J=8.3, 2.1 Hz, 1H), 7.01(dd, J=8.0, 1.3 Hz, 1H), 6.49 (dd, J=6.1, 1.4 Hz, 1H), 6.40 (dd, J=15.9,1.4 Hz, 1H), 6.24 (dd, J=15.9, 6.2 Hz, 1H), 2.22 (s, 3H), 2.02 (s, 3H);¹³C NMR (125 MHz, CDCl₃) δ 169.9, 169.5, 148.3, 136.3, 132.9, 131.9,130.64, 130.60, 130.2, 129.7, 128.7, 128.5, 128.4, 126.6, 126.0, 123.3,70.7, 21.24, 21.18; IR (film): 3063, 3038, 2926, 2852, 1767, 1739, 1608,1587, 1554, 1473, 1454, 1431, 1370, 1233, 1198, 1174, 1133, 1026 cm⁻¹;LRMS (ESI): Mass calculated for [M+H]⁺ C₁₉H₁₇C₁₂O₄: 379.1; found: 379.1.

Example 14

(E)-2-(1-Acetoxy-3-(3-nitrophenyl)allyl)phenyl acetate (1l)

Prepared according to the general procedure using(E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1l as a colorless oil (352 mg, 54%). Analytical data for 1l: ¹H NMR (500MHz, CDCl₃) δ 8.23 (t, J=1.9 Hz, 1H), 8.10 (ddd, J=8.4, 2.3, 1.1 Hz,1H), 7.66 (dt, J=8.0, 1.3 Hz, 1H), 7.57-7.45 (m, 2H), 7.40 (td, J=7.8,1.7 Hz, 1H), 7.30 (td, J=7.6, 1.3 Hz, 1H), 7.12 (dd, J=8.1, 1.3 Hz, 1H),6.65 (d, J=16.0 Hz, 1H), 6.63 (d, J=6.0 Hz, 1H), 6.49 (dd, J=16.0, 5.9Hz, 1H), 2.34 (s, 3H), 2.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9,169.5, 148.7, 148.4, 138.0, 132.6, 130.4, 130.2, 129.8, 129.7 (2C),128.8, 126.6, 123.4, 122.8, 121.4, 70.6, 21.24, 21.20; IR (film): 3087,3068, 3039, 2937, 2869, 2310, 2281, 1825, 1780, 1721, 1656, 1608, 1587,1490, 1431, 1378, 1341, 1262, 1158, 1043, 1023, 975 cm⁻¹; LRMS (ESI):Mass calculated for [M+H]⁺ C₁₉H₁₈NO₆: 356.1; found: 356.2.

Example 15

(E)-2-(1-Acetoxy-3-phenylallyl)-5-fluorophenyl acetate (1m)

Prepared according to the general procedure using(E)-1-(4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1m as a colorless oil (485 mg, 70%). Analytical data for 1m: ¹H NMR (500MHz, CDCl₃) δ 7.48 (dd, J=8.7, 6.2 Hz, 1H), 7.39-7.27 (m, 5H), 6.99(ddd, J=8.6, 7.9, 2.6 Hz, 1H), 6.89 (dd, J=9.1, 2.6 Hz, 1H), 6.60 (d,J=16.0 Hz, 1H), 6.57 (dd, J=6.4, 1.4 Hz, 1H), 6.32 (dd, J=15.9, 6.4 Hz,1H), 2.32 (s, 3H), 2.10 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9,169.0, 162.5 (d, J=249.3 Hz), 149.1 (d, J=10.9 Hz), 136.0, 132.9, 129.9(d, J=9.6 Hz), 128.8, 128.4, 127.2 (d, J=3.6 Hz), 126.8, 126.0, 113.6(d, J=21.3 Hz), 111.2 (d, J=24.4 Hz), 70.7, 21.3, 21.1; ¹⁹F NMR (376MHz, CDCl₃) δ −112.10; IR (film): 3082, 3028, 2938, 1951, 1890, 1732,1651, 1603, 1578, 1504, 1425, 1371, 1235, 1143, 1091 and 1015 cm⁻¹; LRMS(ESI): Mass calculated for [M+H]⁺ C₁₉H₁₈FO₄: 329.1; found: 329.2.

Example 16

(E)-2-(1-Acetoxy-3-phenylallyl)-4-fluorophenyl acetate (1n)

Prepared according to the general procedure using(E)-1-(5-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1n as a yellow oil (382.1 mg, 63%). Analytical data for 1n: ¹H NMR (500MHz, CDCl₃) δ 7.39-7.29 (m, 4H), 7.28-7.24 (m, 1H), 7.22 (dd, J=8.9, 2.8Hz, 1H), 7.10-7.02 (m, 2H), 6.63 (dd, J=15.9, 1.3 Hz, 1H), 6.56 (dd,J=6.8, 1.3 Hz, 1H), 6.28 (dd, J=15.9, 6.6 Hz, 1H), 2.30 (s, 3H), 2.13(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.8, 169.5, 160.4 (d, J=245.3 Hz),144.0 (d, J=2.9 Hz), 135.9, 133.5, 133.1 (d, J=7.4 Hz), 128.8, 128.4,126.8, 125.5, 124.7 (d, J=8.5 Hz), 116.1 (d, J=23.4 Hz), 115.1 (d,J=24.4 Hz), 70.7, 21.3, 21.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.63; IR(film): 3082, 3060, 3028., 2935, 2851, 1766, 1651, 1619, 1579, 1494,1370, 1269, 1205, 1171, 1065, 1017, 968, 941, 901, 879 cm⁻¹; LRMS (ESI):Mass calculated for [M+H]⁺ C₁₉H₁₈FO₄: 329.1; found: 329.1.

Example 17

(E)-2-(1-Acetoxy-3-phenylallyl)-4-methoxyphenyl acetate (1o)

Prepared according to the general procedure using(E)-1-(2-hydroxy-5-methoxyphenyl)-3-phenylprop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1o as a colorless oil (380 mg, 61%). Analytical data for 1o: ¹H NMR (500MHz, CDCl₃) δ 7.37 (d, J=7.0 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.24 (d,J=7.3 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 7.02 (d, J=4.1 Hz, 1H), 6.88 (dd,J=8.9, 3.1 Hz, 1H), 6.62 (dd, J=15.9, 1.3 Hz, 1H), 6.55 (dd, J=6.5, 1.4Hz, 1H), 6.32 (dd, J=15.9, 6.5 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H), 2.12(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.93, 169.91, 157.6, 141.7, 136.1,133.0, 132.0, 128.7, 128.3, 126.8, 126.0, 124.0, 114.2, 113.9, 71.2,55.8, 21.3, 21.1; IR (film): 3086, 3061, 3032, 2999, 2917, 2849, 2832,1608, 1578, 1488, 1433, 1372, 1307, 1269, 1165, 1029 cm⁻¹; LRMS (ESI):Mass calculated for [M+H]⁺ C₂₀H₂₁O₅: 341.1; found 341.1.

Example 18

(E)-1-(2-Acetoxy-3-methylphenyl)-3-phenylallyl acetate (1p)

Prepared according to the general procedure using(E)-1-(2-hydroxy-3-methylphenyl)-3-phenylprop-2-en-1-one. The residuewas purified by flash chromatography using 15% EtOAc/hexanes to afford1p as a yellow oil (280 mg, 47%). Analytical data for 1p: ¹H NMR (500MHz, CDCl₃) δ 7.40-7.15 (m, 8H), 6.62 (dd, J=15.9, 1.4 Hz, 1H), 6.55 (m,1H), 6.36 (dd, J=15.9, 6.5 Hz, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 2.10 (s,3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 169.0, 147.4, 136.2, 131.5,131.4, 131.3, 128.7, 128.2, 127.3, 126.8, 126.5, 126.4, 126.3, 76.2,21.3, 20.9, 16.5; IR (film): 3060, 3027, 2957, 2925, 2855, 1762, 1740,1598, 1577, 1496, 1468, 1437, 1369, 1232, 1209, 1165, 1089, 1016, 966and 907 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺ C₂₀H₂₁O₄: 325.1;found: 325.1.

Example 19 General Procedure for Enantioselective Synthesis of Chromenes

Into an oven-dried, screw-capped reaction tube-vial equipped withmagnetic stirbar was loaded bis-acetate (0.36 mmol, 1 equiv). The vialwas taken into a nitrogen-filled drybox at which time Pd₂(dba)₃ (7.2μmol, 0.02 equiv) and phosphoramidite (29 μmol, 0.08 equiv) were added.The vial was capped with a septum cap, removed from the drybox and putunder positive N₂ pressure. The mixture was diluted with CH₂Cl₂ (3.6 mL)and stirred for 10 min under static nitrogen pressure. A solution ofK₂CO₃ (0.36 mmol, 1 equiv) in methanol:water (1.8 mL:1.8 mL) was added.The resulting biphasic mixture was stirred at 23° C. for 19-48 h.Reaction was extracted with CH₂Cl₂. The combined organic layers werefiltered through a Biotage ISOLUTE® phase separator, and the organicfiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography using EtOAc/hexanes to afford thecorresponding chromene.

Example 20

2-Phenyl-2H-chromene (2a)

Prepared according to the general procedure using 1a. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2a asa light yellow oil (53 mg, 71%). Analytical data for 2a: ¹H NMR (500MHz, CDCl₃) δ 7.52-7.43 (m, 2H), 7.43-7.36 (m, 2H), 7.36-7.31 (m, 1H),7.12 (td, J=7.8, 1.7 Hz, 1H), 7.02 (dd, J=7.5, 1.7 Hz, 1H), 6.87 (td,J=7.4, 1.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.54 (dd, J=9.8, 1.9 Hz,1H), 5.93 (dd, J=3.4, 1.9 Hz, 1H), 5.81 (dd, J=9.8, 3.4 Hz, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 153.5, 141.2, 129.9, 129.1, 128.8, 127.4, 127.0,125.2, 124.4, 121.7, 121.6, 116.4, 77.5; IR (film): 3043, 2919, 2851,1573, 1510, 1485, 1456, 1227, 1201, 1112, 1060, 857 cm⁻¹; HRMS (EI):Mass calculated for [M]⁺ C₁₅H₁₂O: 208.0888; found 208.0869; Enantiomericratio was measured by chiral phase HPLC (Chiralcel OJ-H; 100% hexanes;0.7 mL/min, 280 nm), Rt₁ (minor)=61.4, Rt₂ (major)=74.8 min; er=95:5.The absolute configuration of the chromenes was determined by comparisonof optical rotation to literature value of the known enantiomer.

Example 21

2-(Naphthalen-1-yl)-2H-chromene (2b)

Prepared according to the general procedure using 1b. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2b asa light yellow oil (66 mg, 71%). Analytical data for 2b: ¹H NMR (500MHz, CDCl₃) δ 8.32 (d, J=8.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.84(d, J=8.2 Hz, 1H), 7.65 (dd, J=7.0, 1.1 Hz, 1H), 7.54 (dddd, J=20.2,8.0, 6.7, 1.4 Hz, 2H), 7.45 (dd, J=8.2, 7.1 Hz, 1H), 7.11 (td, J=7.7,1.7 Hz, 1H), 7.08 (dd, J=7.4, 1.6 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H),6.79 (d, J=8.0 Hz, 1H), 6.65 (dd, J=9.7, 2.1 Hz, 1H), 6.62 (t, J=2.7 Hz,1H), 5.92 (dd, J=9.8, 3.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 153.9,135.8, 134.5, 131.3, 129.9, 129.6, 129.2, 127.1, 126.8, 126.24, 126.16,125.7, 125.3, 125.2, 124.4, 122.0, 121.7, 116.6, 75.2; IR (film): 3072,3042, 1640, 1605, 1510, 1485, 1456, 1307, 1228, 1200, 1112, 1060, 1036,1010, 959, 944 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₉H₁₄O:258.1045; found 258.1036; Enantiomeric ratio was measured by chiralphase HPLC (Chiralcel OJ-H; 100% hexanes; 0.7 mL/min, 280 nm), Rt₁(minor)=61.2, Rt₂ (major)=83.9 min; er=94:6.

Example 22

2-(Naphthalen-2-yl)-2H-chromene (2c)

Prepared according to the general procedure using 1c. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2c asa light yellow oil (81 mg, 87%). Analytical data for 2c: ¹H NMR (500MHz, CDCl₃) δ 7.89-7.81 (m, 4H), 7.61 (dd, J=8.5, 1.8 Hz, 1H), 7.52-7.44(m, 2H), 7.12 (td, J=7.8, 1.7 Hz, 1H), 7.04 (dd, J=7.5, 1.6 Hz, 1H),6.88 (td, J=7.5, 1.2 Hz, 1H), 6.81 (dt, J=8.2, 1.0 Hz, 1H), 6.59 (ddd,J=10.0, 1.9, 0.8 Hz, 1H), 6.09 (dd, J=3.4, 1.9 Hz, 1H), 5.88 (dd, J=9.9,3.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 153.3, 138.2, 133.4, 133.3,129.7, 128.8, 128.3, 127.8, 126.8, 126.4 (2C), 126.2, 125.1, 124.8,124.4, 121.5, 121.4, 116.2, 77.4; IR (film): 3072, 1640, 1510, 1228cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₉H₁₄O: 258.1045; found258.1022; Enantiomeric ratio was measured by chiral phase HPLC (Whelk-O;100% hexanes; 0.7 mL/min, 280 nm), Rt₁ (minor)=35.7, Rt₂ (major)=66.8min; er=91:9.

Example 23

2-(o-Tolyl)-2H-chromene (2d)

Prepared according to the general procedure using 1d. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2d asa yellow oil (58 mg, 72%). Analytical data for 2d: ¹H NMR (500 MHz,CDCl₃) δ 7.48 (dt, J=7.0, 1.2 Hz, 1H), 7.24-7.18 (m, 3H), 7.11 (td,J=7.8, 1.7 Hz, 1H), 7.02 (dd, J=7.4, 1.7 Hz, 1H), 6.87 (td, J=7.4, 1.1Hz, 1H), 6.77 (dt, J=8.1, 0.9 Hz, 1H), 6.56 (dd, J=9.8, 2.1 Hz, 1H),6.15 (dd, J=3.1, 2.1 Hz, 1H), 5.75 (dd, J=9.8, 3.2 Hz, 1H), 2.47 (s,3H); ¹³C NMR (125 MHz, CDCl₃) δ 153.6, 138.4, 136.1, 131.0, 129.5,128.5, 127.8, 126.7, 126.3, 124.7, 124.6, 121.5, 121.3, 116.1, 74.8,19.4; IR (film): 3061, 3022, 2971, 2924, 1646, 1633, 1586, 1563, 1485cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₆H₁₄O: 222.1045; found222.1018; Enantiomeric ratio was measured by chiral phase HPLC (Whelk-O;100% hexanes; 0.1 mL/min, 280 nm), Rt₁ (minor)=100.9, Rt₂ (major)=118.5min; er=92:8.

Example 24

2-(p-Tolyl)-2H-chromene (2e)

Prepared according to the general procedure using 1e. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2e asa yellow oil (58 mg, 73%). Analytical data for 2e: ¹H NMR (500 MHz,CDCl₃) δ 7.39-7.35 (m, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.12 (td, J=7.7, 1.7Hz, 1H), 7.03 (dd, J=7.4, 1.7 Hz, 1H), 6.88 (td, J=7.5, 1.2 Hz, 1H),6.80 (dt, J=8.1, 0.9 Hz, 1H), 6.55 (dd, J=9.9, 1.9 Hz, 1H), 5.90 (dd,J=3.4, 1.9 Hz, 1H), 5.81 (dd, J=9.8, 3.4 Hz, 1H), 2.37 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 153.3, 138.4, 138.0, 129.6, 129.5, 127.2, 126.7,125.1, 124.1, 121.5, 121.3, 116.2, 77.4, 21.6; IR (film): 3044, 2958,2851, 1633, 1484 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₆H₁₄O:222.1045; found 222.1015; Enantiomeric ratio was measured by chiralphase HPLC (Chiralcel OJ-H; 100% hexanes; 0.7 mL/min, 280 nm), Rt₁(major)=62.3, Rt₂ (minor)=124.4 min; er=93:7.

Example 25

2-(3-Methoxyphenyl)-2H-chromene (2f)

Prepared according to the general procedure using 1f. The residue waspurified by flash chromatography using 1.5% EtOAc/hexanes to afford 2fas a light yellow oil (67 mg, 78%). Analytical data for 2f: ¹H NMR (500MHz, CDCl₃) δ 7.29 (t, J=7.9 Hz, 1H), 7.14-7.08 (m, 1H), 7.06-6.98 (m,3H), 6.89-6.84 (m, 2H), 6.80 (dt, J=8.0, 0.9 Hz, 1H), 6.55-6.50 (m, 1H),5.91-5.87 (m, 1H), 5.79 (dd, J=9.8, 3.4 Hz, 1H), 3.80 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 160.2, 153.5, 142.8, 130.1, 129.9, 127.0, 125.2,124.4, 121.7, 121.6, 119.7, 116.4, 114.2, 112.9, 55.6, 53.8; IR (film):3043, 3009, 2959, 2834, 1610, 1485, 1286, 1227, 788 cm⁻¹; HRMS (EI):Mass calculated for [M]⁺ C₁₆H₁₄O₂: 238.0994; found 238.0983;Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OJ-H;100% hexanes; 0.7 mL/min, 280 nm), Rt₁ (minor)=102.8, Rt₂ (major)=127.3min; er=94:6.

Example 26

2-(2-Fluorophenyl)-2H-chromene (2g)

Prepared according to the general procedure using 1g. The residue waspurified by flash chromatography using 0.8% EtOAc/hexanes to afford 2gas a light yellow oil (61 mg, 75%). Analytical data for 2g: ¹H NMR (500MHz, CDCl₃) δ7.51 (td, J=7.6, 1.8 Hz, 1H), 7.30 (dddd, J=8.2, 7.2, 5.3,1.8 Hz, 1H), 7.15-7.11 (m, 2H), 7.08 (ddd, J=10.3, 8.3, 1.2 Hz, 1H),7.01 (dd, J=7.5, 1.7 Hz, 1H), 6.88 (td, J=7.4, 1.1 Hz, 1H), 6.81 (dt,J=8.1, 1.0 Hz, 1H), 6.54 (ddd, J=9.9, 1.9, 0.8 Hz, 1H), 6.29 (dd, J=3.6,1.9 Hz, 1H), 5.79 (ddd, J=10.0, 3.6, 1.1 Hz, 1H); ¹³C NMR (125 MHz,CDCl₃) δ 159.6 (d, J=247.4 Hz), 153.2, 130.0 (d, J=8.2 Hz), 129.7, 128.7(d, J=3.9 Hz), 128.1 (d, J=13.4 Hz), 126.8, 124.5 (d, J=3.6 Hz), 124.4,123.8, 121.5, 121.2, 116.1, 115.7 (d, J=21.4 Hz), 71.2 (d, J=3.8 Hz); IR(film): 3044, 2923, 2851, 1641, 1485 cm⁻¹; HRMS (EI): Mass calculatedfor [M]⁺ C₁₅H₁₁FO: 226.0794; found: 226.0808; Enantiomerljic ratio wasmeasured by chiral phase HPLC (Chiralcel OJ-H; 100% hexanes; 0.7 mL/min,280 nm), Rt₁ (minor)=22.2, Rt₂ (major)=35.3 min; er=91:9.

Example 27

2-(4-Fluorophenyl)-2H-chromene (2h)

Prepared according to the general procedure using 1h. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2h asa light yellow oil (69 mg, 84%). Analytical data for 2h: ¹H NMR (500MHz, CDCl₃) δ7.43 (td, J=5.9, 5.3, 1.9 Hz, 2H), 7.12 (td, J=7.8, 1.7 Hz,1H), 7.05 (t, J=8.7 Hz, 2H), 7.02 (dd, J=7.5, 1.7 Hz, 1H), 6.88 (td,J=7.4, 1.1 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 6.56 (dd, J=9.9, 1.9 Hz,1H), 5.90 (dd, J=3.5, 1.9 Hz, 1H), 5.78 (dd, J=9.9, 3.4 Hz, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 162.8 (d, J=246.8 Hz), 153.0, 136.7 (d, J=3.2 Hz),129.7, 129.1 (d, J=8.3 Hz), 126.8, 124.6, 124.4, 121.44, 121.35, 116.2,115.7 (d, J=21.5 Hz), 76.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.75; IR(film): 2922, 2852, 1719, 1603, 1509, 1484, 1457, 1224, 1204 cm⁻¹; HRMS(EI): Mass calculated for [M]⁺ C₁₅H₁₁FO: 226.0794; found: 226.0764;Enantiomeric ratio was measured by chiral phase HPLC (Whelk-O; 100%hexanes; 1.0 mL/min, 280 nm), Rt₁ (minor)=9.5, Rt₂ (major)=10.5 min;er=95:5.

Example 28

2-(3-Chlorophenyl)-2H-chromene (2i)

Prepared according to the general procedure using 1i. The residue waspurified by flash chromatography using 0.6% EtOAc/hexanes to afford 2ias a light yellow oil (71 mg, 81%). Analytical data for 2i: ¹H NMR (500MHz, CDCl₃) δ 7.46 (q, J=1.4 Hz, 1H), 7.34 (qd, J=4.3, 1.5 Hz, 1H),7.32-7.30 (m, 2H), 7.14 (td, J=7.8, 1.7 Hz, 1H), 7.03 (dd, J=7.5, 1.7Hz, 1H), 6.89 (td, J=7.4, 1.2 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.56 (dd,J=9.9, 1.9 Hz, 1H), 5.90 (dd, J=3.5, 1.9 Hz, 1H), 5.78 (dd, J=9.9, 3.4Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 152.9, 142.9, 134.6, 130.1, 129.8,128.6, 127.3, 126.8, 125.2, 124.6, 124.1, 121.6, 121.2, 116.1, 76.4; IR(film): 3048, 2923, 2847, 1638, 1602, 1574, 1483, 1457, 1430, 1349 cm⁻¹;HRMS (EI): Mass calculated for [M]⁺ C₁₅H₁₁ClO: 242.0498; found:242.0508; Enantiomeric ratio was measured by chiral phase HPLC (Whelk-O;100% hexanes; 0.35 mL/min, 280 nm), Rt₁ (minor)=27.0, Rt₂ (major)=31.7min; er=93:7.

Example 29

2-(4-(Trifluoromethyl)phenyl)-2H-chromene (2j)

Prepared according to the general procedure using 1j. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2j asa light yellow oil (66 mg, 84%). Analytical data for 2j: ¹H NMR (500MHz, CDCl₃) δ 7.63 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.14 (td,J=7.8, 1.6 Hz, 1H), 7.02 (dd, J=7.4, 1.6 Hz, 1H), 6.89 (td, J=7.5, 1.1Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.57 (dd, J=9.8, 1.8 Hz, 1H), 5.97 (s,1H), 5.79 (dd, J=9.8, 3.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 152.9,144.8, 130.5 (d, J=32.4 Hz), 129.9, 127.3, 126.9, 125.8 (q, J=3.8 Hz),124.7, 124.1 (d, J=272.0 Hz), 124.0, 121.7, 121.2, 116.1, 76.4; ⁹F NMR(376 MHz, CDCl₃) δ −62.64; IR (film): 3047, 2925, 2854, 1620, 1574,1485, 1457, 1418, 1325 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺C₁₆H₁₁F₃O: 276.0762; found: 276.0736; Enantiomeric ratio was measured bychiral phase HPLC (Chiralcel OJ-H; 100% hexanes; 0.7 mL/min, 280 nm),Rt₁ (minor)=30.8, Rt₂ (major)=44.4 min; er=83:17.

Example 30

2-(3,4-Dichlorophenyl)-2H-chromene (2k)

Prepared according to the general procedure using 1k. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2k asa light yellow oil (74 mg, 74%). Analytical data for 2k: ¹H NMR (500MHz, CDCl₃) δ 7.54 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.29 (dd,J=8.3, 2.1 Hz, 1H), 7.13 (td, J=7.8, 1.7 Hz, 1H), 7.02 (dd, J=7.5, 1.7Hz, 1H), 6.89 (td, J=7.5, 1.1 Hz, 1H), 6.79 (dt, J=8.0, 0.9 Hz, 1H),6.57 (dd, J=9.7, 1.4 Hz, 1H), 5.87 (dd, J=3.6, 1.8 Hz, 1H), 5.76 (dd,J=9.8, 3.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 153.0, 141.3, 133.1,132.7, 131.0, 130.2, 129.5, 127.2, 126.7, 125.2, 123.9, 122.0, 121.4,116.4, 76.0; IR (film): 3076, 2924, 2827, 1641, 1486 cm⁻¹; HRMS (EI):Mass calculated for [M]⁺ C₁₅H₁₀C₁₂O: 276.0109; found: 276.0137;Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OJ-H;100% hexanes; 0.5 mL/min, 280 nm), Rt₁ (major)=78.0, Rt₂ (minor)=133.5min; er=90:10.

Example 31

2-(3-Nitrophenyl)-2H-chromene (2l)

Prepared according to the general procedure using 1l. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 2l asa light yellow oil (65 mg, 71%). Analytical data for 2l: ¹H NMR (500MHz, CDCl₃) δ 8.32 (q, J=1.9 Hz, 1H), 8.18 (ddt, J=8.4, 2.6, 1.3 Hz,1H), 7.81 (dt, J=7.8, 1.5 Hz, 1H), 7.55 (td, J=8.0, 1.8 Hz, 1H), 7.15(tt, J=7.6, 1.7 Hz, 1H), 7.04 (dt, J=7.6, 1.8 Hz, 1H), 6.90 (tt, J=7.5,1.4 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.62 (dt, J=10.0, 1.9 Hz, 1H), 6.02(dd, J=3.7, 1.9 Hz, 1H), 5.83 (ddd, J=9.8, 3.6, 1.7 Hz, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 152.7, 148.5, 143.0, 133.2, 130.0, 129.8, 127.0,125.3, 123.4, 123.3, 122.1, 121.9, 121.2, 116.2, 75.7; IR (film): 3065,3032, 2920, 2845, 1645, 1612, 1587, 1500, 1454, 1432, 1264, 1160, 1138,1105, 1036, 982 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₅H₁₁NO₃:253.0739; found: 253.0715; Enantiomeric ratio was measured by chiralphase HPLC (Whelk-O; 100% hexanes; 0.2 mL/min, 280 nm), Rt₁(minor)=48.0, Rt₂ (major)=51.8 min; er=92:8.

Example 32

7-Fluoro-2-phenyl-2H-chromene (2m)

Prepared according to the general procedure using 1m. The residue waspurified by flash chromatography using 0.5% EtOAc/hexanes to afford 2mas a light yellow oil (56 mg, 69%). Analytical data for 2m: ¹H NMR (500MHz, CDCl₃) δ 7.45-7.32 (m, 5H), 6.96 (dd, J=8.3, 6.4 Hz, 1H), 6.57 (td,J=8.4, 2.5 Hz, 1H), 6.51 (ddd, J=10.0, 3.7, 2.1 Hz, 2H), 5.91 (q, J=3.1,1.9 Hz, 1H), 5.76 (dd, J=9.9, 3.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ163.4 (d, J=246.7 Hz), 154.5 (d, J=12.4 Hz), 140.5, 128.9, 128.7, 127.55(d, J=10.0 Hz), 127.2, 123.6 (d, J=2.6 Hz), 123.3, 117.7 (d, J=3.2 Hz),108.0 (d, J=21.9 Hz), 104.1 (d, J=25.1 Hz), 77.4; IR (film): 3065, 3032,2920, 2845, 1645, 1612, 1587, 1500, 1454, 1432, 1264, 1160, 1137, 1105,1036, 982, 852 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₅H₁₁FO:226.0794; found: 226.0804; Enantiomeric ratio was measured by chiralphase HPLC (Whelk-O; 100% hexanes; 0.2 mL/min, 280 nm), Rt₁(minor)=45.9, Rt₂ (major)=52.6 min; er=90:10.

Example 33

6-Fluoro-2-phenyl-2H-chromene (2n)

Prepared according to the general procedure using in. The residue waspurified by flash chromatography using 0.5% EtOAc/hexanes to afford 2nas white solids (59 mg, 72%). Analytical data for 2n: ¹H NMR (500 MHz,CDCl₃) δ 7.43 (dt, J=6.9, 2.1, 1.6 Hz, 2H), 7.40-7.31 (m, 3H), 6.79 (td,J=8.5, 3.0 Hz, 1H), 6.76-6.69 (m, 2H), 6.49 (dt, J=7.7, 3.1, 2.6 Hz,1H), 5.91-5.85 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 157.4 (d, J=238.3Hz), 149.1 (d, J=1.8 Hz), 140.3, 128.7, 128.6, 127.1, 126.4, 123.6 (d,J=2.1 Hz), 122.3 (d, J=8.4 Hz), 116.9 (d, J=8.1 Hz), 115.5 (d, J=23.2Hz), 112.8 (d, J=23.8 Hz), 77.2; ⁹F NMR (376 MHz, CDCl₃) δ −123.28; IR(film): 3063, 3032, 2954, 2921, 2851, 1639, 1582, 1485, 1455, 1441, 1371cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₅H₁₁FO: 226.0794; found:226.0798; Enantiomeric ratio was measured by chiral phase HPLC(Chiralcel OJ-H; 100% hexanes; 0.7 mL/min, 280 nm), Rt₁ (minor)=66.2,Rt₂ (major)=77.0 min; er=97:3.

Example 34

6-Methoxy-2-phenyl-2H-chromene (2o)

Prepared according to the general procedure using 1o. The residue waspurified by flash chromatography using 1% EtOAc/hexanes to afford 20o asa light yellow oil (68 mg, 80%). Analytical data for 2o: ¹H NMR (500MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.40-7.29 (m, 3H), 6.73 (d, J=8.8 Hz,1H), 6.67 (ddd, J=8.9, 3.1, 1.2 Hz, 1H), 6.59 (dd, J=3.2, 1.2 Hz, 1H),6.54-6.46 (m, 1H), 5.88-5.82 (m, 2H), 3.76 (d, J=1.4 Hz, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 154.1, 147.1, 140.8, 128.8, 128.5, 127.2, 126.0,124.3, 122.2, 116.7, 114.6, 111.9, 77.1, 55.9; IR (film): 3033, 2998,2915, 2831, 1609, 1576, 1490, 1429, 1344, 1307, 1265, 1208, 1158, 1117,1045 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₆H₁₄O₂: 238.0994; found238.0970; Enantiomeric ratio was measured by chiral phase HPLC(Chiralcel OJ-H; 40% IPA/hexanes; 1.0 mL/min, 280 nm), Rt₁ (minor)=23.4,Rt₂ (major)=33.6 min; er=86:14.

Example 35

8-Methyl-2-phenyl-2H-chromene (2p)

Prepared according to the general procedure using 1p. The residue waspurified by flash chromatography using 0.1% EtOAc/hexanes to afford 2pas a light yellow oil (58 mg, 73%). Analytical data for 2p: ¹H NMR (500MHz, CDCl₃) δ 7.45 (d, J=7.5 Hz, 2H), 7.39-7.29 (m, 3H), 6.98 (d, J=7.5Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.77 (t, J=7.5 Hz, 1H), 6.52 (dd,J=9.9, 1.8 Hz, 1H), 5.94 (dd, J=3.7, 1.8 Hz, 1H), 5.82 (dd, J=9.8, 3.6Hz, 1H), 2.16 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.5, 141.6, 131.3,128.9 (2C), 128.5, 127.1 (2C), 125.6, 124.9, 124.7 (2C), 121.3, 120.9,77.0, 16.0; IR (film): 3062, 3044, 3029, 2920, 2851, 1644, 1602, 1494,1455, 1390, 1344, 1304, 1264, 1208, 1178, 1156, 1082, 1055, 1029, 1001,968, 939, 917 cm⁻¹; HRMS (EI): Mass calculated for [M]⁺ C₁₆H₁₄O:222.1045; found 222.1031; Enantiomeric ratio was measured by chiralphase HPLC (Chiralcel OJ-H; 5% IPA/hexanes; 1.0 mL/min, 280 nm), Rt₁(minor)=8.7, Rt₂ (major)=12.5 min; er=85:15.

Example 36 General Procedure for Racemic Synthesis of Chromenes

To a round bottom flask equipped with magnetic stir bar was dissolved2′-hydroxychalcone derivative (0.5 mmol, 1 equiv) in isopropanol (5 mL).Mixture was heated to 70° C. before NaBH₄ (1.5 mmol, 3 equiv.) was addedin one portion and was slowly cooled to 23° C. Ice was added and theresulting solution was acidified using 10% glacial acetic acid to pH 5.The solution was extracted with CH₂Cl₂, organics washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by flash chromatography withEtOAc/hexanes to afford the corresponding chromenes.

Ligand Synthesis Example 37

To a solution of diol (2.94 mmol, 1 equiv) and triethylamine (14.68mmol, 5 equiv) in dry, oxygen-free THF (18 mL) at 0° C. was added PCl₃(3.52 mmol, 1.2 equiv). After stirring for 2 h at 23° C. under positiveN₂ pressure, reaction was cooled to 0° C. before a solution ofpiperidine (5.87 mmol, 2 equiv) in dry, oxygen-free THF (10 mL) wasslowly added via cannula. The resulting mixture was slowly warmed to 23°C. and stirred for 20 h under positive N₂ pressure. Reaction was dilutedwith Et₂O, filtered through a plug of Celite®, and concentrated underreduced pressure. The residue was purified by flash chromatography usingEtOAc/hexanes to afford the corresponding phosphoramidites.

Example 38

1-((5R,6R)-5,6-Dimethoxy-4,4,7,7-tetraphenyl-1,3,2-dioxaphosphepan-2-yl)piperidine(L4)

Prepared according to the general procedure using(2R,3R)-2,3-dimethoxy-1,1,4,4-tetraphenylbutane-1,4-diol. The residuewas purified by flash chromatography using 1% EtOAc/hexanes to afford L4as a white foam (44 mg, 65%). Analytical data for L4: ¹H NMR (500 MHz,CDCl₃) δ 7.73 (d, J=7.0 Hz, 2H), 7.53 (d, J=7.3 Hz, 2H), 7.43 (d, J=7.2Hz, 2H), 7.36-7.18 (m, 14H), 4.50 (dd, J=7.3, 3.6 Hz, 1H), 4.30 (d,J=7.3 Hz, 1H), 3.26 (s, 3H), 3.16 (dtd, J=15.1, 7.0, 3.1 Hz, 2H), 2.83(m, 2H), 2.58 (s, 3H), 1.54-1.37 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ146.6, 146.5, 142.3, 141.92, 141.89, 129.10, 129.08, 128.7, 128.0,127.6, 127.43, 127.39, 127.3, 127.24, 127.22, 126.88, 126.85, 126.8,84.74, 84.69, 83.7, 82.4, 82.3, 81.0, 80.9, 59.7, 59.4, 45.1, 44.9,26.94, 26.91, 25.1; ³¹P NMR (162 MHz, CDCl₃) δ 133.2; IR (film): 3089,3057, 3034, 3024, 2932, 2848, 2831, 1599, 1582, 1492, 1445, 1372, 1334,1316, 1265, 1213, 1184.22 1128, 1041, 974, 947, 805 cm⁻¹; LRMS (ESI):Mass calculated for [M+H]⁺ C₃₅H₃₉NO₄P: 568.3; found 568.4.

Example 39

(3aR,8aR)—N-cyclohexyl-4,4,8,8-tetrakis(3,5-dimethylphenyl)-N,2,2-trimethyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-amine(L3j)

Prepared according to the general procedure using((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(bis(3,5-dimethylphenyl)methanol).The residue was purified by flash chromatography using 1% EtOAc/hexanesto afford L3j as a white foam (195 mg, 77%). Analytical data for L3j: ¹HNMR (500 MHz, CDCl₃) δ 7.45 (s, 2H), 7.21 (s, 2H), 7.06 (d, J=10.2 Hz,4H), 6.88-6.78 (m, 4H), 5.07 (dd, J=8.5, 3.5 Hz, 1H), 4.65 (d, J=8.5 Hz,1H), 3.25 (tdd, J=11.8, 8.2, 3.4 Hz, 1H), 2.81 (d, J=7.6 Hz, 3H), 2.29(s, 6H), 2.27 (s, 6H), 2.26 (s, 12H), 1.88-1.70 (m, 4H), 1.60 (d, J=14.4Hz, 1H), 1.54-1.47 (m, 2H), 1.45 (s, 3H), 1.27 (ddt, J=20.8, 12.7, 3.6Hz, 2H), 1.05 (ddd, J=16.6, 8.4, 3.5 Hz, 1H), 0.22 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 147.5, 147.04, 147.02, 142.3, 142.1, 137.1, 136.8, 136.7,136.3, 129.0, 128.9, 128.8, 128.7, 127.1, 126.64, 126.61, 125.2, 111.2,83.61, 83.59, 83.0, 82.8, 81.2, 81.1, 80.72, 80.70, 57.5, 57.2, 32.60,32.55, 32.5, 32.4, 27.9, 27.6, 27.5, 26.50, 26.48, 25.9, 25.4, 21.84,21.78, 21.7; ³¹P NMR (162 MHz, CDCl₃) δ 140.0; IR (film): 3047, 2990,2930, 2855, 2731, 1787, 1754, 1600, 1450, 1380, 1265, 1214, 1159, 1066,969, 942, 861, 785, 738, 690, 601, 574, 508, 413 cm⁻¹; LRMS (ESI): Masscalculated for [M+H]⁺ C₄₆H₅₉NO₄P: 720.4; found 720.6.

Example 40

1-((3aR,8aR)-4,4,8,8-Tetrakis(3,5-diethylphenyl)-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl)piperidine(L3k)

Prepared according to the general procedure using((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(bis(3,5-diethylphenyl)methanol).The residue was purified by flash chromatography using 1% EtOAc/hexanesto afford L3k as a white foam (2.15 g, 91%). Analytical data for L3k: ¹HNMR (500 MHz, CDCl₃) δ 7.45 (d, J=1.6 Hz, 2H), 7.30 (d, J=1.6 Hz, 2H),7.13 (s, 2H), 7.05 (d, J=1.6 Hz, 2H), 6.92-6.82 (m, 4H), 5.15 (dd,J=8.5, 3.1 Hz, 1H), 4.78 (d, J=8.5 Hz, 1H), 3.38-3.26 (m, 2H), 3.16(ddd, J=15.0, 8.8, 5.4 Hz, 2H), 2.66-2.51 (m, 16H), 1.65-1.51 (m, 6H)1.36 (s, 3H), 1.19 (dtt, J=7.1, 4.3, 2.1 Hz, 24H), 0.18 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 147.2, 146.9, 143.4, 142.9, 142.5, 142.1, 142.0,126.3, 126.2, 126.2, 126.04, 125.99, 125.96, 124.4, 124.3, 110.9, 83.33,83.31, 82.8, 82.7, 81.6, 81.5, 81.3, 45.1, 44.9, 29.1, 29.0, 28.93,28.91, 27.7, 27.2, 27.1, 25.3, 25.1, 15.9, 15.6, 15.4; ³¹P NMR (162 MHz,CDCl₃) δ 137.2; IR (film): 2964, 2933, 2873, 1600, 1459, 1371, 1333,1247, 1215, 1160, 1072, 1038, 949, 875, 853, 783, 739, 703, 506, 432,411 cm⁻¹; LRMS (ESI): Mass calculated for [M+H]⁺ C₅₂H₇₁NO₄P: 804.5;found 804.5.

Example 41 Synthesis of [Pd(η³-1,3-diphenylallyl){(S,S)-L3g}]BF₄Bis[(μ-chloro)(η³-1,3-diphenylallyl)palladium(II)]

Prepared according to procedure described by Pregosin and co-workers.(P. Barbaro, A. Currao, J. Herrmann, R. Nesper, P. S. Pregosin, and R.Salzmann, Organometallics, 1996, 15, 1879-1888.) PdCl₂ (350 mg, 1.95mmol) and LiCl (350 mg, 8.3 mmol) were stirred in H₂O (2.3 mL) for 45min. Ethanol (3.9 mL) and (rac)-(E)-3-acetoxy-1,3-diphenyl-1-propene (1g, 3.97 mmol) in THF (11 mL) were then added, and the brown solution wascooled to 0° C. After the addition of 1.2 mL of concentrated HCl, carbonmonoxide was slowly bubbled through the solution for 15 min. Another 0.8mL of concentrated HCl was added and CO bubbled for 1.5 h. The stream ofCO was then stopped and the solution stirred under CO atmosphere for 7 hat 23° C. The yellow mixture was filtered, washed with MeOH and Et₂O,and dried under vacuum overnight. Spectroscopic data was consistent withthose previously reported.

Example 42 [Pd(η³-1,3-diphenylallyl){(S,S)-L3g)]}BF₄

To a solution of bis[(μ-chloro)(η³-1,3-diphenylallyl)palladium(II)] (12mg, 0.018 mmol) in anhydrous acetone was added (S,S)-L3g (25 mg, 0.035mmol). The mixture was stirred for 2 h at 23° C. To the yellow solutionwas added a solution of silver tetrafluoroborate (7.59 mg, 0.039 mmol)in THF. The filtrate was concentrated at reduced pressure, and CH₂Cl₂was added. Pentane was carefully layered on top to inducecrystallization and afford [Pd(η³-1,3-diphenylallyl){(S,S)-L3g}]BF₄ asyellow needles.

Synthetic Transformations Example 43

(2R,3S)-2-Phenylchroman-3-ol (7)

A solution of 2-phenyl-2H-chromene (2a) (167 mg, 0.8 mmol) and 1 molarBH₃-THF (16 mL) was stirred for 2 h at 23° C. Solution was cooled to 0°C. before a 20% (w/w) aqueous solution of NaOH (4.8 mL) and 30% (w/w)aqueous solution of H₂O₂ (4.9 mL) were added. The reaction was slowlywarmed to 23° C. and stirred for 12 h. The solution was then dilutedwith Et₂O and H₂O followed by acidification with 10% (w/w) aqueous HCland extraction with Et₂O. The organics were combined, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.Purification by flash chromatography with 10% EtOAc/hexanes afforded 7as a white solid (115 mg, 63%). Spectroscopic data was consistent withthose previously reported.

Example 44

(2R,3S)-2-Phenylchroman-3-yl 3,4,5-trihydroxybenzoate (8)

Prepared using a modified literature procedure. (J. C. Anderson, R. A.McCarthy, S. Paulin and P. W. Taylor, Bioorg. Med. Chem. Lett., 2011,21, 6996-7000.) To a solution of (2R,3S)-2-phenylchroman-3-ol (7) (91mg, 0.4 mmol) in CH₂Cl₂ (2 mL) was added DMAP (28 mg, 0.23 mmol), Et₃N(0.167 mL, 1.2 mmol) and tri-OBn gallic acid chloride (184 mg, 0.4mmol). The reaction was stirred for 12 h at 23° C., washed with H₂Ofollowed by brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The protected gallate ester wastaken up in EtOAc (4 mL). To the solution was added 10 wt. % Pd/C (255mg, 2.4 mmol). The mixture was stirred under an atmosphere of H₂ for 14h, filtered through a plug of Celite®, dried over sodium sulfate,filtered, and concentrated under reduced pressure. Purification by flashchromatography with 30% EtOAc/hexanes afforded 8 as a white solid (89mg, 59%). Analytical data for 8: ¹H NMR (500 MHz, CDCl₃) δ 7.40 (dd,J=7.5, 1.8 Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.21(td, J=7.8, 7.4, 1.7 Hz, 1H), 7.10 (s, 2H), 7.09-7.05 (m, 1H), 7.01 (dd,J=8.2, 1.2 Hz, 1H), 6.93 (td, J=7.4, 1.2 Hz, 1H), 5.70 (bs, 1H), 5.55(td, J=6.0, 4.9 Hz, 1H), 5.46 (bs, 2H), 5.33 (d, J=5.7 Hz, 1H), 3.11(dd, J=16.7, 4.8 Hz, 1H), 2.96 (dd, J=16.6, 6.1 Hz, 1H); ¹³C NMR (125MHz, CDCl₃) δ 143.1, 138.2, 129.8, 128.6, 128.3, 127.9, 126.2, 121.0,116.5, 109.9, 78.4, 69.9, 28.6. Other spectroscopic data was consistentwith those previously reported.

Example 45

(2R,3S,4S)-2-(3-Chlorophenyl)chromane-3,4-diol (9)

To a solution of 2-(3-chlorophenyl)-2H-chromene (2i) (72.8 mg, 0.3 mmol)and 4-methylmorpholine N-oxide (52.7 mg, 0.45 mmol) in THF (3 mL) andwater (0.116 mL) was added a 2.5 wt % solution of osmium tetraoxide int-BuOH (0.118 mL). The mixture was stirred at 23 C for 16 h and was thenquenched with a saturated solution of sodium thiosulfate. The mixturewas extracted with EtOAc. The combined organics was washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude was purified by flash chromatography using 20%EtOAc/hexanes to afford 9 as an off-white solid (76 mg, 91%). Analyticaldata for 9: ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.48 (m, 1H), 7.39 (dd,J=7.6, 1.7 Hz, 1H), 7.37 (d, J=1.4 Hz, 3H), 7.30 (ddd, J=8.6, 7.3, 1.7Hz, 1H), 7.02 (td, J=7.4, 1.2 Hz, 1H), 6.96 (dd, J=8.2, 1.1 Hz, 1H),5.05 (d, J=9.5 Hz, 1H), 4.81 (t, J=3.7 Hz, 1H), 4.04 (ddd, J=9.5, 6.6,3.7 Hz, 1H), 2.57 (d, J=3.7 Hz, 1H), 2.25 (d, J=6.6 Hz, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 154.0, 139.9, 134.8, 130.9, 130.7, 130.1, 129.0,127.8, 125.9, 122.0, 121.7, 117.0, 76.2, 71.1, 66.2; IR (film): 3407,2919, 2851, 1583, 1485, 1455, 1239, 1036, 1012, 754, 701, 511 cm⁻¹; LRMS(ESI): Mass calculated for [M+H]⁺ C₁₅H₁₄ClO₃: 277.1; found 277.1.

Example 46

(2R,3R)-2-(3-Chlorophenyl)-3-hydroxychroman-4-one (10)

To a solution of (2R,3S,4S)-2-(3-chlorophenyl)chromane-3,4-diol (9) (28mg, 0.1 mmol) in CH₂Cl₂ (2 mL) was added manganese dioxide (44 mg, 0.5mmol). The mixture was stirred at 23° C. for 24 h, filtered through aplug of Celite®, and concentrated under reduced pressure. The crude waspurified by flash chromatography using 7% EtOAc/hexanes to afford 10 asa solid (16 mg, 59%). Analytical data for 9: ¹H NMR (500 MHz, CDCl₃) δ7.93 (dd, J=7.9, 1.7 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.58 (ddd, J=8.6,7.2, 1.8 Hz, 1H), 7.48-7.45 (m, 1H), 7.42-7.38 (m, 2H), 7.14 (ddd,J=8.0, 7.2, 1.0 Hz, 1H), 7.07 (dd, J=8.4, 1.0 Hz, 1H), 5.12 (d, J=12.3Hz, 1H), 4.57 (dd, J=12.3, 1.9 Hz, 1H), 3.70 (d, J=1.9 Hz, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 193.8, 161.5, 138.3, 137.1, 134.6, 129.9, 129.4,127.6, 127.4, 125.8, 122.4, 118.4, 118.1, 83.0, 73.6; IR (film): 3461,2921, 2851, 2361, 2341, 1695, 1608, 1579, 1466, 1300, 1229, 1138, 1104,1009, 861, 764, 693, 419, 405 cm⁻¹; LRMS (ESI): Mass calculated for[M+H]⁺ C₁₅H₁₂ClO₃: 275.0; found 275.1.

While the principles of this invention have been described in connectionwith certain embodiments, it should be understood clearly that thesedescriptions are provided only by way of example and are not intended tolimit, in any way, the scope of this invention. For instance, thepresent invention can be applied to arylallyl-substituted phenoxy esterstarting materials where R can be one or more C₁-C₆ alkyl and/or alkoxymoieties and Ar can be substituted with one or more C₁-C₆ alkyl and/oralkoxy moieties to provide corresponding 2-aryl chromene compounds.Other advantages and features of this invention will become apparentfrom the claims hereinafter, with the scope of such claims determined bythe reasonable equivalents as would be understood by those skilled inthe art.

We claim:
 1. A composition comprising compounds of a formula

wherein R is selected from H, halo, alkyl and alkoxy moieties and Ar isselected from phenyl and substituted phenyl moieties, said phenylsubstituents selected from halo, alkyl, alkoxy, nitro and haloalkylsubstituents, multiple said substituents and combinations thereof, saidcomposition comprising at least about 70% an enantiomer of a formula


2. The composition of claim 1 wherein said phenyl moiety is selectedfrom methyl, a methoxy, fluoro, chloro, nitro and dichloro substitutedphenyl moieties, said composition comprising at least about 90% saidenantiomer.